The present invention relates to the manufacture of a capsule containing a biologically active medium, intended to be implanted in a living organism for therapeutic purposes. In the conventional way, a capsule of this type consists of a core comprising a biologically active medium, which is surrounded by a semipermeable casing. The role of the casing is to isolate the biologically active medium from the tissues of the receiving organism while at the same time allowing substances via which the implanted capsule fulfils its functions to pass through the casing. By way of example, when the biologically active medium is a suspension of cells, the semipermeable casing must act as a barrier to immune reactions, must allow nutrients to diffuse towards the core of the capsule and must allow the substance of therapeutic benefit secreted by the cells (insulin, for example, when the cells are islets of Langerhans) to diffuse towards the organism.
From the point of view of the efficiency of the exchanges across the membrane, it would seem that spherical capsules are preferred over tubular capsules. However, spherical capsules have the drawback of being difficult to locate when implanted, which means that at the present time it would not be possible to implant them in a human body from which the implants have always to be able to be extracted for reasons of biological safety.
Recent research has therefore been mainly centred on manufacturing tubular capsules, which allow the shaping of implants that are long enough that they can be easily found. In particular, it has been discovered that it is preferable to segment the tubular capsules, that is to say to form therein compartments which are isolated from one another, so that if part of an implanted capsule is damaged, it is possible to separate it from the implant and extract it from the receiving organism.
U.S. Pat. No. 5,158,881 describes a method of manufacturing a segmented tubular capsule, comprising the steps of:
coextruding a polymer solution intended to form the casing of the capsule and a biologically active medium by simultaneously injecting the polymer solution and the biologically active medium through a die, and
interrupting the injection of the biologically active medium at determined points in time to form in the fibre successive compartments full of the biologically active medium and separated by a solid partition section consisting only of the polymer solution.
This method does not yield the desired results when the polymer solution is liquid because, when the injection of biologically active medium is interrupted, a drop of polymer solution forms under the die, deforms and breaks under the effect of the weight of the fibre already formed which hangs from the die.
The object of the invention is to improve the above-described method in such a way as to make it possible to manufacture a segmented tubular capsule from a liquid polymer solution. Another object of the invention is to shape a tubular capsule into a shape that can be directly implanted.
To achieve this objective, there is provided, according to the invention, a method of manufacturing a tubular capsule comprising a wall delimiting internal compartments that are isolated from one another, the wall being made from a solution of at least one polymer and the compartments being full of a biologically active medium, the method comprising:
coextruding the solution of at least one polymer and the biologically active medium by simultaneously injecting the polymer solution and the biologically active medium through a die of determined dimensions,
interrupting the injection of the biologically active medium at determined points in time to form in the fibre successive compartments full of the biologically active medium and separated by a partition section made of the polymer solution:
causing partial early solidification of the fibre as it leaves the die to a sufficient extent to prevent the fibre from breaking at the partition sections.
As a preference, partial early solidification of the fibre may include:
immersing the fibre in a coagulation liquid as it leaves the die so as to initiate early coagulation of the polymer solution around the outside of the fibre; and
simultaneously driving the fibre through the coagulation liquid along a determined path.
This method may have at least two major benefits. On the one hand, it makes it possible to envisage industrial-scale or semi-industrial-scale implant production. On the other hand, bringing the fibre leaving the die into early contact with the coagulation liquid allows some of the solvent used to prepare the polymer solution to be extracted, which is something that is particularly desirable to be extracted, which is something that the particularly desirable when the biologically active medium contains living cells which may be adversely affected by the solvents commonly used.
According to one feature of the invention, the method further comprises, at the same time as partially solidifying the fibre, exerting a determined tensile force on the fibre so as to give it at least one geometric characteristic that is independent of the dimensions of the die.
By virtue of this arrangement, it is possible to extrude low viscosity polymer solutions.
According to another feature of the invention, the method furthermore comprises giving the fibre a permanent shape. For example, the fibre is wound onto a cylindrical mandrel in such a way as to adopt the shape of a spiral, the pitch of which is chosen to be such that each section of the fibre comprising a whole number of compartments corresponding to an implantable capsule occupies a determined length of mandrel.
By virtue of this arrangement, the dimensions of the implantable capsule can be adjusted to suit the size of the receiving organism. It has been found that the spiral-wound shape was particularly well-suited to implants in that it gave them mechanical robustness, in that it made them easier to handle and in that it made them easier to implant in an organism.
Another subject of the invention is a device for manufacturing a tubular fibre comprising a wall delimiting internal compartments isolated from one another and full of a biologically active medium, comprising:
extrusion means of determined dimensions for coextruding a solution of at least one polymer and the biologically active medium in such a way as to obtain a tubular fibre having a wall made from the polymer solution and filled with the biologically active medium;
means for supplying the extrusion means with the polymer solution and with the biologically active medium;
means for controlling the simultaneous supply of the extrusion means with polymer solution and with biologically active medium and for interrupting the supply of biologically active medium at determined points in time so as to form within the fibre successive compartments filled with the biologically active medium and separated by a solid partition section consisting only of the polymer solution;
the device being characterized in that it comprises:
means for causing partial solidification of the fibre as it leaves the extrusion means, this solidification being enough to prevent the fibre from breaking at the partition sections.
As a preference, the solidification means comprise:
a bath for a coagulation liquid placed under the extrusion means at a chosen distance so that a fibre flowing out from the die at a given output rate begins to coagulate early from the outside and does not break; and
means for driving the fibre through the coagulation liquid along a determined path.
According to one feature of the invention, the device further comprises means for exerting a determined tensile force on the fibre so as to give it at least one geometric characteristic that is independent of the dimensions of the extrusion means.
In one embodiment of the invention, the driving means and the means for exerting a tensile force comprise a tube passing through the bottom of the coagulation bath and having an upper end inside the bath and a lower end outside the bath, this tube being arranged substantially vertically and its upper end lying below the surface of the coagulation liquid when the bath is filled to a determined operating level.
This embodiment is particularly advantageous because it allows several functions to be fulfilled using very simple and inexpensive technical means. Furthermore, it is easy to regulate and allows very low tensile forces to be exerted on the fibre, if appropriate.
According to one feature of the invention, the device further comprises means for giving the fibre a determined shape. For example, the shape chosen is a spiral and the means for giving the fibre this shape comprise:
a mandrel made up of disassemble portions;
means for rotating the mandrel;
a guiding device for moving the fibre with a back and forth movement parallel to the mandrel.
Advantageously, in operation, the rotational speed of the mandrel and the speed of the back and forth movement of the guiding device are chosen so that the portion of fibre wound in a spiral onto the length of a portion of mandrel corresponds approximately to a determined whole number of internal compartments of the fibre.
By virtue of this arrangement, it is possible to limit the handling of the shaped fibre as far as possible: all that is required is to ensure that the length of fibre needed to form an implantable capsule is wound onto each mandrel portion. When the fibre is wound along the entire length of the mandrel, the fibre is cut at the junction between two contiguous mandrel portions and the mandrel portions are separated and can act as supports for the implantable capsules during despatch and storage.
Other features and advantages of the invention will become clear from reading the description which follows.